As the smoking generation is aged and their average life expectancy is prolonged, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, diffuse panbronchiolitis, intrinsic asthma, etc. are considered to be major diseases in respiratory diseases in the future.
It is revealed that smoking can be an evident causative factor of chronic obstructive pulmonary disease. Obstructive disorders proceed by smoking, and the degree of the disorders depends on the number of cigarettes smoked. Specifically, the disorders proceed more easily as smoking is initiated at an early age. In addition, a dose correlation between smoking and bronchial gland hyperplasia has been confirmed.
In animal experiments, there are many reports that emphysematous change can be caused by smoking.
Physiological changes in chronic obstructive pulmonary disease (hereinafter abbreviated sometimes as COPD) are characterized with unique abnormal findings observed in 3 regions, that is, central airway, peripheral airway, and lung parenchyma. In lesions in the central airway, hyperplasia of goblet cells and morphological change in secretary tissues such as growth and hypertrophy of cells in submucosal glands are observed. With respect to inflammatory cells, an increase in macrophages and activated T lymphocytes is indicated in the airway mucus. As lesions in the region of bronchiole, mucus plugging in the airway lumen, abnormal formation of goblet cells in the airway epithelium, infiltration of inflammatory cells in the airway wall, and thickening and fibrosis of smooth muscles are observed. In alveolar parenchyma, pulmonary emphysema lesions defined by destruction and disappearance of alveolus and expansion of the air space are observed. Imbalance between protease and antiprotease is considered involved in these lesions. Any of these physiological changes cause airway obstruction.
Cholesterol 25-hydroxylase (CH25H) (GenBank Accession NO. NM—003956) is one kind of cholesterol hydroxylase and has an activity of converting cholesterol into 25-hydroxycholesterol (25-HC) (J. Biol. Chem. 273:34316-34327 (1998)). The product 25-hydroxycholesterol is known to induce interleukin-β in macrophage (Eur. J. Clin. Invest. 32:35-42 (2002)).
Prostate differentiation factor (GDF15, PLAB) (GenBank Accession NO. AF003934) has an effect of promoting a neutrophil infiltration action via interleukin 8 (J. Immunol. 171:2057-2065 (2003)).
Matrix metalloproteinase 19 (MMP19) (GenBank Accession NO. U38321) is an enzyme having a proteolysis enzyme activity (J. Biol. Chem. 272:4281-4286 (1997)).
Under these circumstances, there is desire for the development of prophylactic/therapeutic agents for respiratory diseases (for example, chronic obstructive pulmonary disease etc.), which are excellent with less side effects, as well as diagnostic agents for respiratory diseases.